The present invention provides an efficient process for the preparation of chiral trans-2,3-disubstituted 5-oxotetrahydropyrans of structural formula (I):
wherein Ar is phenyl optionally substituted with one to five R1 substituents;each R1 is independently selected from the group consisting of:
fluorine,
chlorine,
C1-6 alkyl, optionally substituted with one to five fluorines, and
C1-6 alkoxy, optionally substituted with one to five fluorines;
and P is a primary amine protecting group.
The present invention also provides intermediates useful in the disclosed process.
The synthesis of tetrahydropyran-3-ones of structural formula (I) has previously been described in PCT international patent application WO 2007/126745, which published on Nov. 18, 2007. In this publication, the pyranone was elaborated in a racemic 10-step sequence involving heating a nitroketone with 3-iodo-2-(iodomethyl)prop-1-ene and further chemical manipulation. Resolution of the racemic product was achieved by chiral chromatography.
In the present invention, chiral intermediates of structural formula (I) are produced in an efficient enantioselective manner starting from a lower alkyl N-(diphenylmethylene)glycinate. The process involves a one-pot elaboration of a Weinreb amide, generation of an optionally substituted phenyl ketone, transfer hydrogenation of the ketone with installation of two stereogenic centers through a highly enantioselective ruthenium (Ru) metal-catalyzed dynamic kinetic resolution (DKR) asymmetric transfer hydrogenation, a rhodium (Rh)— or ruthenium-metal catalyzed cycloisomerization to construct the dihydropyran skeleton, hydroboration with oxidative work-up to generate a pyran-5-ol, and oxidation to afford the desired pyranone final product of formula (I).